Synthetic routes to treprostinil N-acyl methylsulfonamide

Article abstract of DOI:10.1016/j.tetlet.2019.151428

The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.

Full text of DOI:10.1016/j.tetlet.2019.151428

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic routes to treprostinil N-acyl methylsulfonamide
Christina Picken a,b, Peter Laing a,b, Lei Shen , Lucie H. Clapp , Steve Brocchini b,
a
a,
⇑
⇑
a
Institute of Cardiovascular Sciences, University College London, Gower Street, London WC1E 6BT, UK
School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from
treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also
achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall
yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting
group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide
Received 26 September 2019
Revised 15 November 2019
Accepted 19 November 2019
Available online xxxx
1
4 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds
Chemical compounds:
Treprostinil (PubChem CID6918140)
Triol (PubChem CID11174966)
greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil
N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacy-
clin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Prostacyclin
Treprostinil
Acylsulfonamide
Prodrug
Introduction
Pulmonary arterial hypertension (PAH) is a chronic inflamma-
tory disease of the small pulmonary capillaries, characterised by
vasoconstriction, cell proliferation and fibrosis [1] which increases
pulmonary arterial pressure resulting in heart failure and ulti-
mately death [2]. Reduced endogenous prostacyclin 1 is implicated
in the aetiology and progression of PAH [3,4] leading to the use of
prostacyclin 1 to treat PAH (see Fig. 1) [5–7]. Prostacyclin 1 acts at
the prostacyclin (IP) receptor, also termed the prostaglandin I
2
receptor. Despite its potent vasodilatory, antiproliferative and
anti-platelet properties, prostacyclin 1 is chemically and metabol-
ically unstable [8–10].
Fig. 1. Structures of endogenous prostacyclin 1 and treprostinil 2.
Treprostinil 2 is a stable prostacyclin mimetic shown to allevi-
ate symptoms and slow disease progression in patients (see
Fig. 1) [11,12]. As with all prostacyclin analogues, treprostinil 2
has dose-limiting toxicities [13]. Treprostinil 2 can be administered
by continuous ambulatory pump to provide a controlled dose
through a subcutaneous catheter [14].
Infusion site pain is principally attributed to the affinity of trepros-
tinil at the IP receptor but may possibly involve additional prosta-
noid receptors such as the EP and DP receptors which are also
2 1
located in the skin [16,17], and would be activated at similar con-
centrations to the IP receptor by treprostinil [9].
The presence of the treprostinil carboxylic acid moiety is impor-
tant for maintaining biological activity at the IP receptor [18]. Sev-
eral treprostinil carboxylic acid esters have been evaluated but no
treprostinil prodrugs have been clinically registered [19–23], pre-
sumably due to the action of endogenous esterases leading to the
premature release of treprostinil [24].
Despite improved clinical efficacy, the subcutaneous adminis-
tration of treprostinil is associated with pain at the infusion site
[
15] which can lead to patients withdrawing from therapy [13].
⇑
Corresponding authors.
E-mail addresses: l.clapp@ucl.ac.uk (L.H. Clapp), s.brocchini@ucl.ac.uk (S.
Brocchini).
https://doi.org/10.1016/j.tetlet.2019.151428
0
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: C. Picken, P. Laing, L. Shen et al., Synthetic routes to treprostinil N-acyl methylsulfonamide, Tetrahedron Letters, https://doi.org/
0.1016/j.tetlet.2019.151428
1

2
C. Picken et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 2. Structure of the prodrug selexipag 3 that is cleaved by hepatic enzymes to give the metabolite ACT-333679 4 which is a potent IP receptor agonist.
amide 6 (Scheme 1) using either carbodimidazole (CDI) or N-(3-
0
dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDCI)
resulted in multiple products as determined by TLC analysis, which
1
were difficult to isolate. H NMR and HPLC analysis of the crude
product mixtures suggested that a significant amount of trepros-
tinil 2 had not undergone reaction. Efforts to prepare the
N-hydroxysuccinimide ester of treprostinil were similarly unsuc-
1
cessful (determined by TLC and H NMR). A protecting group
strategy appeared to be necessary to avoid possible side reactions
due to the treprostinil secondary hydroxyls.
Treprostinil protecting group strategies have been described in
the patent literature [32–35]. These strategies rely on the simulta-
neous protection of the carboxylic acid and the two secondary
hydroxyls, which would then be followed by subsequent selective
deprotection of the carboxylic acid. Several methods were evalu-
ated (ESI Table S1) but did not generate sufficient yields of pure
product. One strategy to per-trimethylsilylate treprostinil [35]
using N,O-bis(trimethysilyl)acetimidate to give the tri-silylated
treprostinil adduct, relied on the lability of the trimethylsilyl ester
to allow coupling of methanesulfonamide 6 to give the desired tre-
prostinil N-acyl methylsulfonamide 5. A treprostinil-derived pro-
Fig. 3. Structure of treprostinil N-acyl methylsulfonamide 5.
The orally administered non-prostanoid, N-acyl methylsulfon-
amide pro-drug called selexipag 3 (marketed as UPTRAVI) [25]
had a 13-fold lower affinity for the IP-receptor than the active form
of the drug (ACT-333679 4; Fig. 2) [26,27]. Upon absorption of
selexipag 3 into the bloodstream, the N-acyl methylsulfonamide
moiety is cleaved by hepatic carboxyesterases to unmask the
active drug 4 exhibiting efficacy for treating PAH [28–30]. Selexi-
pag 3 was designed to reduce side effects caused by the direct acti-
vation of IP receptors before absorption into the bloodstream [28].
N-Acylsulfonamides are known to exhibit chemical and biolog-
ical stability making them desirable candidates for prodrug struc-
tures [31]. We considered that a N-acyl methylsulfonamide form
of treprostinil would combine the extended-release characteristics
of a drug such as selexipag with the desirable pharmacological pro-
file of treprostinil to reduce unwanted activity upon administra-
tion and ultimately achieve greater tolerability. We sought to
prepare treprostinil N-acyl methylsulfonamide 5, which we
hypothesise will have lower activity at the IP receptor compared
to treprostinil 2 (see Fig. 3).
1
duct was isolated but analysis by H NMR did not confirm the
presence of the desired product.
Attempts to directly benzylate the two hydroxyls in treprostinil
2
using an excess of different bases and benzyl bromide, resulted in
no reaction or the formation of several products within which the
desired bis-hydroxyl benzylate treprostinil product was observed
in small amounts. To avoid competitive reactions with the trepros-
tinil carboxylic acid moiety, treprostinil ethyl ester 7 could be pre-
pared in good yield (88%) by Fisher esterification, allowing for
benzylation of the secondary alcohols to again be examined (ESI
Table S1). Benzylation of treprostinil and the corresponding ethyl
ester proved difficult owing to the poor nucleophilicity of the sec-
ondary alcohols. It was found that when treprostinil ethyl ester 7
was treated with the Dudley reagent (2-benzyloxy-1-methylpri-
dinium triflate) [36] dissolved in dichloromethane (DCM) the
desired bis-benzyl treprostinil ethyl ester 8 (Scheme 2) was formed
as a yellow oil in 49% yield following isolation by column chro-
matography. Following successful benzylation, direct benzylation
of treprostinil using the Dudley reagent was also attempted and
showed efficient conversion as determined by TLC.
Results and discussion
The preparation of treprostinil N-acyl methylsulfonamide 5 by
directly coupling treprostinil 2 (50 mg scale) and methylsulfon-
Scheme 1. Proposed direct conversion of treprostinil 2 to treprostinil N-acyl methylsulfonamide 5.
Please cite this article as: C. Picken, P. Laing, L. Shen et al., Synthetic routes to treprostinil N-acyl methylsulfonamide, Tetrahedron Letters, https://doi.org/
0.1016/j.tetlet.2019.151428
1

C. Picken et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 2. Synthesis of treprostinil N-acyl methylsulfonamide 5 from treprostinil 2. (i) Dudley reagent, MgO, trifluorotoluene; (ii) LiOH, MeOH/THF/water; (iii) methane
sulfonamide 6, carbodiimidazole, 1,8-Diazabicyclo[5.4.0]undec-7-ene, DCM; (iv) Pd/C, H , EtOH. Isolated yields are shown.
2
Scheme 3. Triol 12 has potential to add to the carboxylic acid head group and prodrug moiety in one step. (A) The synthesis of treprostinil 2 from the triol precursor 12 by
reaction with chloroacetonitrile 13. (B) The formation of treprostinil N-acyl methylsulfonamide 5 required at least 2 equiv of sodium hydride for bromoacetyl
acylmethylsulfonamide 14 to undergo reaction with triol 12. (C) The treprostinil triethylene glycol ester analogue 16 was synthesised from the ethylene glycol bromoacetyl
bromide 15 and the triol 12 in mild basic conditions. Isolated yields are shown.
Hydrolysis of the ethyl ester 8 was conducted using LiOH in
THF/methanol/water to give the bis-benzyl treprostinil 9 (89%)
needed for coupling with methanesulfonamide 6. Coupling was
achieved using two different reagents reported in the literature
THF at reflux gave the desired bis-benzyl treprostinil N-acyl
methylsulfonamide 10 (NMR, MS) in 21% yield after column chro-
matography. Secondly, N-(3-dimethylaminopropyl)-N -ethylcar-
bodiimide hydrochloride (EDCI) and dimethylaminopyridine
(DMAP) in dichloromethane (DCM) at room temperature [38]
0
[
37]. Firstly, carbonyldiimidazole (CDI) in the presence of DBU in
Please cite this article as: C. Picken, P. Laing, L. Shen et al., Synthetic routes to treprostinil N-acyl methylsulfonamide, Tetrahedron Letters, https://doi.org/
0.1016/j.tetlet.2019.151428
1

4
C. Picken et al. / Tetrahedron Letters xxx (xxxx) xxx
afforded the desired product in 46% yield following purification by
column chromatography. Benzyl deprotection gave treprostinil N-
acyl methylsulfonamide 5 (64%).
prostinil N-acyl methylsulfonamide 5 was evaluated over the con-
centration range of 0.01–1000 nM in HEK-293 cells expressing the
human IP receptor. The log concentration causing 50% of the max-
imal response (log EC50) for cyclic AMP generation was 30-fold
lower for treprostinil N-acyl methylsulfonamide 5 compared to
treprostinil 2 (Fig. 4). This EC50 value for treprostinil was similar
to that calculated previously in the same cell line [42]. The 30-fold
difference in the EC50 of treprostinil N-acyl methylsulfonamide 5
and treprostinil 2 is double that of selexipag and ACT-333679
(13-fold difference) as measured in a similar cyclic AMP assay [27].
Employment of a stable prodrug with reduced activity for the
parenteral administration of treprostinil is hypothesised to avoid
premature drug release which is predicted to translate clinically
to a reduction in side effects experienced upon administration.
With a favourable stability profile, a prodrug strategy may also
enable a depot administration rather than continuous infusion.
Moreover, treprostinil N-acyl methylsulfonamide 5 (like selexipag
3) may be amenable to oral dosing, with concomitant advantages
of therapeutic ratio and convenience of administration. These fea-
tures remain to be established in further research. The encouraging
results presented indicate that in vivo studies are warranted.
Although the overall yield could be improved by direct benzyla-
tion, the majority of losses occurred during the coupling of trepros-
tinil 5 to methane sulfonamide 6. Since treprostinil is an expensive
starting material, the cumulative losses due to protection and
deprotection steps, and the low efficiency of the coupling reactions
of methanesulfonamide 6, are not optimal for preparing trepros-
tinil N-acyl methylsulfonamide 5. The triol precursor 12 under-
went selective alkylation at the aryl hydroxy with
chloroacetonitrile 13 followed by hydrolysis to give treprostinil 2
(Scheme 3A) [39].
To avoid the aforementioned limitations, we found that it was
possible to prepare treprostinil N-acyl methylsulfonamide 5 in
0% isolated yield after purification by the alkylation of the triol
2
precursor 12 with the bromo-sulfonamide adduct 14 using excess
NaH (Scheme 3B) [40]. Excess NaH was required due to the acidic
proton in the bromo-sulfonamide 14 to give the desired trepros-
tinil N-acyl methylsulfonamide 5. The product structure was con-
1
firmed by H NMR spectroscopy (Fig. S1). Alkylation of the triol
precursor 12 with an a-bromo ester (e.g. ester 15, Scheme 3C) that
does not have an acidic proton adjacent to the carbonyl, as does
bromo-sulfonamide 14, is easily accomplished in good yield
Acknowledgements
(
>80%) using potassium carbonate in acetone at reflux as described
We are grateful to the Biotechnology and Biological Science
Research Council (BBSRC grant number BB/L015803/1) and Lung
Biotechnology PBC (Silver Spring, MD, USA) for funding this project
and the CASE PhD studentship for CP. We are also grateful to Uni-
ted Therapeutics Corporation (Research Triangle Park, NC, USA) for
supplying samples of the triol intermediate 12 and treprostinil 2.
by Kokotos and co-workers [41].
The overall yield to prepare treprostinil N-acyl methylsulfon-
amide 5 directly from the triol precursor 12 is similar to the pro-
tecting group strategies starting from treprostinil 2 because
deprotonation of the acidic proton in bromoacetyl acylmethylsul-
fonamide 14 reduces the electrophilicity for alkylation to the triol
1
2. The treprostinil triol precursor 12 is useful however for the
preparation of a variety of prodrug candidates using a wide range
of -halo derivatives (e.g. ethylene glycol bromoacetyl bromide
5).
The biological effects of IP agonists can be evaluated by the con-
Appendix A. Supplementary data
a
1
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151428.
version of ATP to cyclic AMP in stable cells expressing the IP recep-
tor [4,42]. In vivo, an increase in intracellular cyclic AMP results in
a vasodilatory, anti-proliferative and anti-thrombotic response [9].
The concentration-dependent response of treprostinil 2 and tre-
References
[1] R.T. Schermuly, H.A. Ghofrani, M.R. Wilkins, F. Grimminger, Nat. Rev. Cardiol. 8
(
2011) 443–455.
[
2] G. Simonneau, N. Galiè, L.J. Rubin, D. Langleben, W. Seeger, G. Domenighetti, S.
Gibbs, D. Lebrec, R. Speich, M. Beghetti, S. Rich, A. Fishman, J. Am. Coll. Cardiol.
43 (2004) 5S–12S.
[
[
[
[
[
3] R. Del Pozo, I. Hernandez Gonzalez, P. Escribano-Subias, Expert Rev. Respir.
Med. 11 (2017) 491–503.
4] E. Falcetti, S.M. Hall, P.G. Phillips, J. Patel, N.W. Morrell, S.G. Haworth, L.H.
Clapp, Am. J. Respir. Crit. Care Med. 182 (2010) 1161–1170.
5] L.J. Rubin, J. Mendoza, M. Hood, M. McGoon, R. Barst, W.B. Williams, J.H. Diehl,
J. Crow, W. Long, Ann. Intern Med. 112 (1990) 485.
6] L.J. Rubin, B.M. Groves, J.T. Reeves, M. Frosolono, F. Handel, A.E. Cato,
Circulation 66 (1982) 334–338.
7] R.J. Barst, L.J. Rubin, W.A. Long, M.D. McGoon, S. Rich, D.B. Badesch, B.M.
Groves, V.F. Tapson, R.C. Bourge, B.H. Brundage, S.K. Koerner, D. Langleben, C.A.
Keller, S. Murali, B.F. Uretsky, L.M. Clayton, M.M. Jöbsis, S.D. Blackburn, D.
Shortino, J.W. Crow, N. Engl. J. Med. 334 (1996) 296–301.
[
[
8] L.H. Clapp, J. Patel, Int. J. Respir. Care 6 (2010) 27–33.
9] L.H. Clapp, R. Gurung, Prostaglandins Other Lipid Mediat. 120 (2015) 56–71.
[
10] M. Humbert, N.W. Morrell, S.L. Archer, K.R. Stenmark, M.R. MacLean, I.M. Lang,
B.W. Christman, E.K. Weir, O. Eickelberg, N.F. Voelkel, M. Rabinovitch, J. Am.
Coll. Cardiol. 43 (2004) 13S–24S.
[
[
11] F. Torres, L.J. Rubin, Expert Rev. Cardiovasc. Ther. 11 (2013) 13–25.
12] V.F. Tapson, C.J. Sanchez Diaz, G.M. Bohns Meyer, T. Pulido, P. Sepulveda, K.Y.
Wang, C.Q. Deng, R. Grover, D. Solum, A. Ousmanou, R.J. White, J. Heart Lung
Transplant. 38 (2019) S94–S95.
[
[
13] M.S. Kingman, S. Lombardi, J. Infus. Nurs. 37 (2014) 442–451.
14] K. Laliberte, C. Arneson, R. Jeffs, T. Hunt, M. Wade, J. Cardiovasc. Pharmacol. 44
Fig. 4. Concentration–response relationship of intracellular cyclic AMP changes
induced by treprostinil 2 and treprostinil N-acyl methylsulfonamide 5 in HEK-293
cells stably transfected with the human IP receptor. Cyclic-AMP concentration
(
2004) 209–214.
[
15] C. Picken, K.C. Fragkos, M. Eddama, G. Coghlan, L.H. Clapp, C. Picken, K.C.
Fragkos, M. Eddama, G. Coghlan, L.H. Clapp, J. Clin. Med. 8 (2019) 481.
16] K. Kabashima, M. Nagamachi, T. Honda, C. Nishigori, Y. Miyachi, Y. Tokura, S.
Narumiya, Lab Investig. 87 (2007) 49–55.
(
mean ± SEM; n = 4) was measured following drug treatment (15 min) and
normalised to cell protein content. Data points were fit with a unity sigmoidal-
curve using Prism software. The concentration giving a half-maximal response
[
(
EC50) for treprostinil 2 and treprostinil N-acyl methylsulfonamide 5 (SUL-TREP)
[17] H. Hohjoh, T. Inazumi, S. Tsuchiya, Y. Sugimoto, Biochimie 107 (2014) 78–81.
[18] B.J.R. Whittle, S. Moncada, Prog. Med. Chem. 21 (1985) 237–279.
was 0.59 nM and 18 nM, respectively.
Please cite this article as: C. Picken, P. Laing, L. Shen et al., Synthetic routes to treprostinil N-acyl methylsulfonamide, Tetrahedron Letters, https://doi.org/
0.1016/j.tetlet.2019.151428
1

C. Picken et al. / Tetrahedron Letters xxx (xxxx) xxx
5
[
[
[
19] F. Leifer, D. Omiatek, V. Malinin, J. Ong, Z. Li, P. Klecha, R. Chapman, D. Salvail,
[31] S. Huang, P.J. Connolly, R. Lin, S. Emanuel, S.A. Middleton, Bioorg. Med. Chem.
Lett. 16 (2006) 3639–3641.
[32] R. Shorr, M. Rothblatt, M. Bentley, D. Michael, X. Zhao, PCT/US2000/008240,
2000.
[33] U. Hershel, H. Rau, T. Lessman, N. Bisek, G. Maitro, K. Sprogoe, T. Wegge, O.
Kiel, J. Zettler, 2013024052, 2013.
[34] V. Malinin, W. Perkin, F. Leifer, D. Konicek, Z. Li, Z. Plaunt, WO2015061720,
2015.
[35] K. Sprogoe, H. Rau, U. Hersel, T. Wegge, O. Keil, J. Zettler, 2013024051, 2013.
[36] S.S. Lopez, G.B. Dudley, Beilstein J. Org. Chem. 4 (2008) 44.
[37] K. Rikimaru, T. Wakabayashi, H. Abe, T. Tawaraishi, H. Imoto, J. Yonemori, H.
Hirose, K. Murase, T. Matsuo, M. Matsumoto, C. Nomura, H. Tsuge, N. Arimura,
K. Kawakami, J. Sakamoto, M. Funami, C.D. Mol, G.P. Snell, K.A. Bragstad, B.-C.
Sang, D.R. Dougan, T. Tanaka, N. Katayama, Y. Horiguchi, Y. Momose, Bioorg.
Med. Chem. 20 (2012) 3332–3358.
C. Laurent, W. Perkins, Eur. Respir. J. 44 (2014) P2356-.
20] United Therapeutics, United Therapeutics, NIH Clin. https://clinicaltrials.gov/
ct2/show/NCT02149095 (accessed April 20, 2018).
21] M.R. Corboz, Z. Li, V. Malinin, A.J. Plaunt, D.M. Konicek, F.G. Leifer, K.-J. Chen, C.
E. Laurent, H. Yin, M.C. Biernat, D. Salvail, J. Zhuang, F. Xu, A. Curran, W.R.
Perkins, R.W. Chapman, J. Pharmacol. Exp. Ther. 363 (2017) 348–357.
22] D. Han, C. Fernandez, E. Sullivan, D. Xu, W. Perkins, M. Darwish, C. Rubino, in:
[
[
[
4
.3 Pulmonary Circulation and Pulmonary Vascular Diseases, vol. 48, European
Respiratory Society, PA 2403, 2016.
23] R.W. Chapman, V. Malinin, D. Konicek, F. Leifer, Z. Li, J. Zhuang, F. Xu, W.R.
Perkins, in: American Thoracic Society International Conference Meetings
Abstracts, Denver, 2017, A52.
24] Ascendis Pharma A/S, Ascendis Pharma A/S, Press Release. https://www.
prnewswire.com/news-releases/ascendis-pharma-as-announces-results-of-
phase-1-study-of-transcon-treprostinil-300073527.html (accessed April 20,
[38] M.M. Lorion, F.J.S. Duarte, M.J. Calhorda, J. Oble, G. Poli, Org. Lett. 18 (2016)
1020–1023.
2
018).
[
[
[
25] European Medicines Agency, Uptravi (selexipag): Summary of Product
Characteristics, London, 2016.
26] T. Asaki, K. Kuwano, K. Morrison, J. Gatfield, T. Hamamoto, M. Clozel, J. Med.
Chem. 58 (2015) 7128–7137.
27] K. Kuwano, A. Hashino, T. Asaki, T. Hamamoto, T. Yamada, K. Okubo, K.
Kuwabara, J. Pharmacol. Exp. Ther. 322 (2007) 1181–1188.
28] A. Nakamura, T. Yamada, T. Asaki, Bioorg. Med. Chem. 15 (2007) 7720–7725.
29] A. Ammazzalorso, B. De Filippis, L. Giampietro, R. Amoroso, Chem. Biol. Drug
Des. 90 (2017) 1094–1105.
[39] R.M. Moriarty, N. Rani, L.A. Enache, M.S. Rao, H. Batra, L. Guo, R.A. Penmasta, J.
P. Staszewski, S.M. Tuladhar, O. Prakash, D. Crich, A. Hirtopeanu, R. Gilardi, J.
Org. Chem. 69 (2004) 1890–1902.
[40] R.C. Oslund, N. Cermak, M.H. Gelb, J. Med. Chem. 51 (2008) 4708–4714.
[41] G. Kokotos, A.J. Feuerherm, E. Barbayianni, I. Shah, M. Sæther, V. Magrioti, T.
Nguyen, V. Constantinou-Kokotou, E.A. Dennis, B. Johansen, J. Med. Chem. 57
[
[
(2014) 7523–7535.
[42] B.J. Whittle, A.M. Silverstein, D.M. Mottola, L.H. Clapp, Biochem. Pharmacol. 84
(2012) 68–75.
[
30] G. Simonneau, A. Torbicki, M.M. Hoeper, M. Delcroix, K. Karlócai, N. Galiè, B.
Degano, D. Bonderman, M. Kurzyna, M. Efficace, R. Giorgino, I.M. Lang, Eur.
Respir. J. 40 (2012) 874–880.
Please cite this article as: C. Picken, P. Laing, L. Shen et al., Synthetic routes to treprostinil N-acyl methylsulfonamide, Tetrahedron Letters, https://doi.org/
0.1016/j.tetlet.2019.151428
1